Date on Master's Thesis/Doctoral Dissertation

5-2017

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

Davis, Keith R

Committee Co-Chair (if applicable)

States, J. Christopher

Committee Member

States, J. Christopher

Committee Member

Ceresa, Brian

Committee Member

Yaddanapudi, Kavitha

Committee Member

Clark, Geoffrey

Author's Keywords

lunasin; melanoma; cancer stem cells; integrins; histone acetylation

Abstract

Lunasin is a 44 amino acid peptide that has been shown to have cancer chemopreventative and chemotherapeutic properties. This study investigated the potential utility of Lunasin as a chemotherapeutic in melanomas. Studies showed that Lunasin had little activity against established melanoma cell lines using adherent culture methods; however, Lunasin’s in vitro activity was significantly higher in non-adherent colony-forming assays and oncosphere formation. These results led to the investigation of whether or not Lunasin has selective effects on cancer initiating cells (CIC) that are known to be present in melanomas. It was revealed that Lunasin selectively inhibited the proliferation of high-ALDH expressing CICs, and prevented oncosphere formation. In vitro results were extended into mouse xenograft studies using parental cells and isolated CICs. Lunasin significantly inhibited tumor growth in both cases, with the highest inhibition being observed in tumors initiated by CICs while achieving an excellent safety profile. Lunasin reduced the invasive potential of CICs in vitro and in an in vivo experimental metastasis model. Mechanistic studies revealed that Lunasin may disrupt integrin signaling by inhibiting phosphorylations of the intracellular kinase FAK as well as altering the PI3K/AKT axis. Additionally, it was demonstrated that histone acetylation in H3 and H4 core histone are significantly altered in CICs treated with Lunasin. While histone acetylation is potentially involved in Lunasin’s anticancer activity, the effects seen in these studies are mainly integrin-driven. These studies demonstrate that Lunasin has activity against putative CICs, and that Lunasin has potential utility as a therapeutic in treating malignant melanomas.

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